Safety data from UPLIFT: Phase I/II study of CDK4/6 inhibition with abemaciclib to upregulate PSMA expression prior to ¹⁷⁷ Lu-PSMA-617 treatment in patients with metastatic castrate resistant prostate cancer (mCRPC).

163 Background: 177 Lu-PSMA-617, a PSMA-targeting radioligand therapy, has shown robust responses in patients with mCRPC that correlate with PSMA expression. A CRISPR screen identified CDK4/6 as a key regulator of PSMA, and CDK4/6 inhibition induced PSMA upregulation in prostate cancer cell lines. The Phase I/II UPLIFT trial is investigating lead-in treatment with the CDK4/6 inhibitor abemaciclib with the goal of upregulating PSMA expression immediately prior to treatment with 177 Lu-PSMA-617 in patients with mCRPC (NCT05113537). Safety data from the phase I portion of the study investigating dose escalation of abemaciclib is presented here. Methods: Eligible patients (pts) had mCRPC which had progressed on a prior ARSI with or without taxane chemotherapy, with PSMA-avid disease (≥3 lesions with PSMA uptake greater than liver). Pts were enrolled to a 3+3 dose escalation of abemaciclib at 3 dose levels (100 mg BID, 150 mg BID, 200 mg BID). With each 6-week cycle, abemaciclib was given as a 14-day lead-in treatment prior to standard administration of 177 Lu-PSMA-617 (7.4 GBq (±10%) per cycle), for up to 4 cycles. 68 Ga-PSMA-11 PET scans were obtained pre and post abemaciclib treatment during cycle 1 to assess changes in PSMA expression. DLTs were assessed during the first cycle (6 weeks) of combination treatment. Primary endpoints of the phase I portion were safety profile of the combination regimen and determination of the recommended phase II dose (RP2D) of abemaciclib in combination with 177 Lu-PSMA-617. Results: Nine patients were enrolled in phase I (3 at each dose level). Median age was 69 (range 60-84), 78% were Caucasian, median baseline PSA was 40.6 ug/L (range 0-744), and 8 pts (89%) had prior taxane chemotherapy. Treatment related adverse events (TRAEs) were reported by all 9 pts, with G3 TRAEs in 22% (2 pts; syncope, PE). Most common TRAEs were fatigue (n=6, 67%), diarrhea (n=5, 56%) and dry mouth (n=4, 44%) (see Table). No G4-5 TRAEs were reported. One pt passed away while on trial from an event unrelated to treatment (CVA). No dose-limiting toxicities (DLTs) were noted at any of the 3 dose levels. The RP2D of abemaciclib as part of this regimen was established at 200 mg BID. Conclusions: Abemaciclib 14 day lead-in treatment prior to 177 Lu-PSMA-617 was well tolerated and deemed safe in patients with mCRPC, with a RP2D of 200 mg BID abemaciclib. The Phase II portion of the trial is ongoing to assess PSMA upregulation on scans during cycle 1 and the potential efficacy of this combination. Clinical trial information: NCT05113537 . TRAE (Most Common) Grade 1 Grade 2 All Grades Fatigue 5 (56%) 1 (11%) 6 (67%) Diarrhea 3 (33%) 2 (22%) 5 (56%) Dry Mouth 4 (44%) 0 4 (44%) Nausea 1 (11%) 2 (22%) 3 (33%) Anemia 1 (11%) 2 (22%) 3 (33%) Constipation 3 (33%) 0 3 (33%) Decreased appetite 2 (22%) 1 (11%) 3 (33%)